Epirubicin Hydrochloride (Page 3 of 8)

5.5 Hepatic

The major route of elimination of epirubicin is the hepatobiliary system [see Clinical Pharmacology (12.3)]. Evaluate serum total bilirubin and AST levels before and during treatment with epirubicin hydrochloride injection. Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients [see Dosage and Administration (2.2)]. Patients with severe hepatic impairment have not been evaluated; therefore, do not use epirubicin hydrochloride injection in this patient population.

5.6 Renal

Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine greater than 5 mg/dL [see Dosage and Administration (2.2)]. Patients undergoing dialysis have not been studied.

5.7 Tumor-Lysis Syndrome

As with other cytotoxic agents, epirubicin hydrochloride injection may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome.

5.8 Immunosuppressant Effects/Increased Susceptibility to Infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving epirubicin hydrochloride injection. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

5.9 Gastrointestinal

Epirubicin hydrochloride injection is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of epirubicin hydrochloride injection, particularly when given in conjunction with other emetigenic drugs [see Adverse Reactions (6.2)].

5.10 Thrombophlebitis and Thromboembolic Phenomena

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of epirubicin hydrochloride injection.

5.11 Coadministration with Cimetidine

Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with epirubicin hydrochloride injection [see Clinical Pharmacology (12.3)].

5.12 Pregnancy

Epirubicin hydrochloride injection can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of epirubicin hydrochloride injection in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods [see Use In Specific Populations (8.1)].

5.13 Male Fertility and Reproductive Outcomes

Males with female sexual partners of childbearing potential should use contraception during and after cessation of epirubicin hydrochloride injection therapy. Epirubicin hydrochloride injection may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain [see Nonclinical Toxicology (13.1)].

5.14 Laboratory Testing

Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with epirubicin hydrochloride injection. Perform repeated evaluations of LVEF during therapy [see Warnings and Precautions (5.5 and 5.6)].

5.15 Inflammation following Irradiation

As with other anthracyclines, administration of epirubicin hydrochloride injection after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation.

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) [see Clinical Studies (14.1)] evaluating epirubicin hydrochloride injection-containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose epirubicin hydrochloride injection regimen (FEC-100/CEF-120), 280 patients received the lower-dose epirubicin hydrochloride injection regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 1.

Table 1. Clinically Relevant Acute Adverse Events in Patients with Early Breast Cancer
Event % of Patients
FEC-100/CEF-120 FEC-50 CMF
(N=620) (N=280) (N=360)
Grades Grades Grades Grades Grades Grades
1 to 4 3/4 1 to 4 3/4 1 to 4 3/4
FEC & CEF = cyclophosphamide + epirubicin hydrochloride injection + fluorouracil; CMF = cyclophosphamide + methotrexate + fluorouracil; NA = not available Grade 1 or 2 changes in transaminase levels were observed but were more frequently seen with CMF than with CEF.
Hematologic
Leukopenia 80.3 58.6 49.6 1.5 98.1 60.3
Neutropenia 80.3 67.2 53.9 10.5 95.8 78.1
Anemia 72.2 5.8 12.9 0 70.9 0.9
Thrombocytopenia 48.8 5.4 4.6 0 51.4 3.6
Endocrine 71.8 0 69.3 0 67.7 0
Amenorrhea 38.9 4.0 5.4 0 69.1 6.4
Hot flashes
Body as a Whole
Lethargy 45.8 1.9 1.1 0 72.7 0.3
Fever 5.2 0 1.4 0 4.5 0
Gastrointestinal
Nausea/vomiting 92.4 25.0 83.2 22.1 85.0 6.4
Mucositis 58.5 8.9 9.3 0 52.9 1.9
Diarrhea 24.8 0.8 7.1 0 50.7 2.8
Anorexia 2.9 0 1.8 0 5.8 0.3
Infection
Infection 21.5 1.6 15.0 0 25.9 0.6
Febrile neutropenia NA 6.1 0 0 NA 1.1
Ocular
Conjunctivitis/keratitis 14.8 0 1.1 0 38.4 0
Skin
Alopecia 95.5 56.6 69.6 19.3 84.4 6.7
Local toxicity 19.5 0.3 2.5 0.4 8.1 0
Rash/itch 8.9 0.3 1.4 0 14.2 0
Skin changes 4.7 0 0.7 0 7.2 0

Delayed Events

Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials.

Table 2. Long-Term Adverse Events in Patients with Early Breast Cancer
% of Patients
Event
FEC-100/CEF-120 FEC-50 CMF
(N=620) (N=280) (N=360)
*In study MA-5, cardiac function was not monitored after 5 years.
Cardiac events
Asymptomatic drops in LVEF 2.1* 1.4 0.8*
CHF 1.5 0.4 0.3
Leukemia
AML 0.8 0 0.3

Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving epirubicin hydrochloride injection. However, an association between anthracyclines such as epirubicin hydrochloride injection and ALL has not been clearly established.

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